Feeding-dependent activation of enteric cells and sensory neurons by lymphatic fluid: evidence for a neurolymphocrine system

Abstract

GW. Feeding-dependent activation of enteric cells and sensory neurons by lymphatic fluid: evidence for a neurolymphocrine system. Am J Physiol Gastrointest Liver Physiol 306: G686 -G698, 2014. First published February 27, 2014 doi:10.1152/ajpgi.00433.2013.-Lymphatic fluid is a plasma filtrate that can be viewed as having biological activity through the passive accumulation of molecules from the interstitial fluid. The possibility that lymphatic fluid is part of an active self-contained signaling process that parallels the endocrine system, through the activation of G-protein coupled receptors (GPCR), has remained unexplored. We show that the GPCR lysophosphatidic acid 5 (LPA5) is found in sensory nerve fibers expressing calcitonin gene-related peptide (CGRP) that innervate the lumen of lymphatic lacteals and enteric nerves. Using LPA5 as a model for nutrient-responsive GPCRs present on sensory nerves, we demonstrate that dietary protein hydrolysate (peptone) can induce c-Fos expression in enterocytes and nerves that express LPA5. Mesenteric lymphatic fluid (MLF) mobilizes intracellular calcium in cell models expressing LPA5 upon feeding in a time-and dose-dependent manner. Primary cultured neurons of the dorsal root ganglia expressing CGRP are activated by MLF, which is enhanced upon LPA5 overexpression. Activation is independent of the known LPA5 agonists, lysophosphatidic acid and farnesyl pyrophosphate. These data bring forth a pathway for the direct stimulation of sensory nerves by luminal contents and interstitial fluid. Thus, by activating LPA5 on sensory nerves, MLF provides a means for known and yet to be identified constituents of the interstitial fluid to act as signals to comprise a "neurolymphocrine" system. G protein-coupled receptor; intestine; lacteal; lysophosphatidic acid 5; nutrient sensing NUTRIENT SENSING IS INCREASINGLY being recognized as affecting the etiology of diseases resulting from obesity, inflammation, dysregulation of intracellular metabolism, and modification of behavior such as food intake.

Luminal chemosensing in the gastroduodenal mucosa

“…Extrinsic afferent nerves originating in the nodose ganglia densely innervate the antrum and duodenal lamina propria [55] and also in the lumen of lymphatic lacteals [56]. Williams et al recently demonstrated that GLP-1 receptor-expressing nodose neurons were mostly stretch sensors innervating the stomach, whereas the GPR65-expressing population innervated duodenal villi and responded to luminal nutrients [57**].…”

“…Williams et al recently demonstrated that GLP-1 receptor-expressing nodose neurons were mostly stretch sensors innervating the stomach, whereas the GPR65-expressing population innervated duodenal villi and responded to luminal nutrients [57**]. In addition to specific receptors associated with EEC-released hormones such as 5-HT, CCK, and GLP-2, afferent neurons possess nutrient receptors, including LPA5, mGluRs, and FFA3 [56;58;59]. Sensory nerves in the subepithelial space likely receive EEC signals and directly detect absorbed nutrients.…”

Pharmacological Tools to Activate Microglia and their Possible use to Study Neural Network Patho-physiology

“…Interestingly, LPA5 (GPR92) is expressed almost exclusively in microglia [ 379 , 380 ] and is barely detectable in astrocytes [ 381 , 382 ]. LPA5 is also expressed by peripheral neurons and their nerves [ 65 , 383 ] as well as by neurons in the spinal cord [ 65 ]. However, we are aware of no publications regarding LPA5 expression in neurons located in other regions of the CNS.…”

Duodenal luminal nutrient sensing

“…Recently, Poole et al [11 •• ] identified LPA5 expression on sensory nerves in the jejunal mucosa, in submucosal and myenteric plexuses, and in primary afferent neurons of dorsal root ganglia of mouse, rat, and human. These authors suggested a novel pathway where molecules, including peptides, in the mesenteric lymphatic fluid (MLF) directly activate LPA5 receptors on sensory nerves.…”

“…These authors suggested a novel pathway where molecules, including peptides, in the mesenteric lymphatic fluid (MLF) directly activate LPA5 receptors on sensory nerves. MLF may provide signals to comprise a ‘neurolymphocrine’ system in which nerve fibers of the lacteal are part of a visceral sensory system that may function separately from those of the vagus, perhaps through primary spinal afferent nerves [11 •• ]. Irrespective of this, peptone-stimulated GLP-1 release was not reduced in GPR92/93 knockout mice [7 •• ], suggesting that this alternative sensory pathway is less important, than the canonical sensing mechanism, at least in mice.…”